Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: NPP30006 Title: An Open-Label Study to Evaluate the Safety of Lamotrigine in Subjects with Painful Diabetic Neuropathy Rationale: The current open-label study was initiated to evaluate the long-term safety (up to 40 weeks) of LTG in subjects with painful diabetic neuropathy (PDN). Phase: III Study Period: 04 April September 2004 Study Design: Open-label, uncontrolled Centres: 52 in the United States Indication: Painful diabetic neuropathy Treatment: In the preceding double-blind studies subjects were randomized to receive LTG 200, 300, or 400mg/day or matching placebo. In order to maintain the treatment blind in NPP30004/NPP30005, subjects who previously participated in NPP30004 or NPP30005 had their dose adjusted as necessary in a blinded fashion through Week 5 so that by Week 6 all subjects began receiving LTG 200mg/day. During Weeks 7 and 8, the subjects increased their daily dose by weekly increments of 100mg/day based on tolerability. After the subject had reached the highest tolerated dose or 400mg/day, the subject continued on that dose for the remainder of the study. After completing the Maintenance Phase or if terminated after Week 5, subjects tapered off investigational product during the first week of the Follow-up Phase (100mg BID on Days 1-3 of taper and 50mg BID on Days 4-6 of taper). Subjects who had not participated in the double-blind study, but who met enrollment criteria following completion of the NPP30006 Baseline Phase, initiated open-label treatment at Visit 1 of the Dose-Adjustment Phase. Subjects received LTG daily doses of 25mg during Weeks 1-2, 50mg during Weeks 3-4, 100mg at Week 5, and 200mg at Week 6. Thereafter, treatment regimens were as described above. Objectives: The primary objective was to assess the long-term (up to 40 weeks) safety of open-label LTG in subjects with pain associated with diabetic neuropathy. Primary Outcome Variable: See Safety Secondary Outcome/Efficacy Variable(s): Secondary efficacy endpoints were change from baseline in the SF- McGill total pain quality, affective and sensory scores; change from baseline in the neuropathy pain scale (NPS) score; proportion of subjects who were much improved or very much improved in the Patient Global Impression of Change (PGIC) and also in the Clinician Global Impression of Change (CGIC). Health outcome assessments included change from baseline in: Short Form-36 (SF-36) health status scores, Profile of Mood States (POMS) scores, Center for Epidemiologic Studies Depression Scale (CES-D) scores, Brief Pain Inventory (BPI) scores, and time lost from Workplace Productivity and Social Activity (WPSA) scores Statistical Methods: Adverse events were classified by body system and Medical Dictionary for Regulatory Affairs (MedDRA) preferred term and were tabulated by treatment group, maximum intensity, seriousness, and attributability to study drug. Summary statistics of clinical laboratory evaluations (hematology, biochemistry, and urinalysis) data were generated. Change from baseline vital sign data (blood pressure, heart rate, and respiratory rate) and ECG interval data (HR, PR, QRS, QT, QTc) were summarized using 95% Confidence Intervals (CI). Secondary efficacy endpoints: change from baseline in the SF-McGill total pain quality, affective and sensory scores; change from baseline in NPS score were summarized using 95% CIs; proportion of subjects who were much improved or very much improved in PGIC and CGIC were also summarized. The Safety Population comprised all subjects who took at least one dose of study drug. The Intent-to-Treat (ITT) Efficacy Population comprised all subjects who took at least one dose of study drug and provided at least one baseline and at least post-baseline efficacy measurement. Study Population: Male or female subjects 18 years of age who had completed the Maintenance Phase of a double-blind study of LTG (NPP30004 or NPP30005) or met the following criteria: a diagnosis of type 1 or type 2 diabetes mellitus; screening hemoglobin A1c level 11% and stable glycemic control for 3 months prior to study entry; diabetic neuropathy at screening defined by bilateral decreased or absent reflexes at the ankles or bilateral decreased vibration, pinprick, fine touch or temperature perception in the distal lower extremities; pain associated with diabetic neuropathy for 6 months, but 5 years; mean pain score 4 during Baseline Phase using an 11-point numerical rating scale, and at least four pain observations recorded on the Baseline diary. All Subjects Number of Subjects: Planned, N 358 Randomised, N 495

2 Completed, n (%) 252 (51) Total Number Subjects Withdrawn, N (%) 243 (49) Withdrawn due to Adverse Events n (%) 88 (18) Withdrawn for other reasons n (%) 155 (31%) Demographics N (Safety) 491 Females: Males, n 215:276 Mean Age, years (SD) 59.9 (10.44) White, n (%) 421 (86) Primary Outcome Results(s): See Safety Secondary Outcome Variable(s): PGIC: Patient Global Impression of Change Rated as improved or very much improved at study exit visit (termination), n (%) 278 (58) CGIC: Clinician Global Impression of Change Rated as improved or very much improved at study exit visit (termination), n (%) 261 (54) NPS: Neuropathy Pain Scale Pain intensity (question # 1) Mean Baseline Score (SD) 6.2 (2.24) Mean Score at exit visit (termination) 3.5 (2.68) Mean Change from Baseline (SD) -2.7 (3.23) 95% Confidence interval (CI) of mean -3.0, -2.4 Total NPS Scores Mean Baseline Score (SD) 5.2 (1.81) Mean Score at exit visit (termination) 3.0 (2.18) Mean Change from Baseline (SD) -2.2 (2.37) 95% Confidence interval (CI) of mean -2.4, -2.0 SF-McGill Total pain quality score Mean Baseline Score (SD) 15.3 (9.89) Mean Score at exit visit (termination) 10.0 (9.27) Mean Change from Baseline (SD) -5.2 (10.60) 95% Confidence interval (CI) of mean -6.2, -4.3 Affective pain quality score Mean Baseline Score (SD) 12.2 (7.39) Mean Score at exit visit (termination) 8.0 (7.09) Mean Change from Baseline (SD) -4.2 (8.20) 95% Confidence interval (CI) of mean -4.9, -3.4 Sensory pain quality score Mean Baseline Score (SD) 3.0 (3.12) Mean Score at exit visit (termination) 2.0 (2.63) Mean Change from Baseline (SD) -1.7 (3.32) 95% Confidence interval (CI) of mean -1.3, -0.8 Health Outcome Analyses SF-36 health outcome status scores Health status Mean Baseline Score (SD) (12.539) Mean change from baseline at exit visit (termination); (SD) (18.319) 95% CI of mean -5.22, Physical functioning Mean Baseline Score (SD) (26.582) Mean change from baseline at exit visit (termination); (SD) ( ) 95% CI of mean -7.78, Role physical Mean Baseline Score (SD) (40.484) Mean change from baseline at exit visit (termination); (SD) ( )

3 95% CI of mean , Bodily pain Mean Baseline Score (SD) (18.599) Mean change from baseline at exit visit (termination); (SD) (22.061) 95% CI of mean , General health Mean Baseline Score (SD) (21.521) Mean change from baseline at exit visit (termination); (SD) ( ) 95% CI of mean -4.51, Vitality Mean Baseline Score (SD) (22.076) Mean change from baseline at exit visit (termination); (SD) (19.229) 95% CI of mean -8.78, Social functioning Mean Baseline Score (SD) (26.494) Mean change from baseline at exit visit (termination); (SD) (27.433) 95% CI of mean -5.89, Role emotion Mean Baseline Score (SD) (40.172) Mean change from baseline at exit visit (termination); (SD) 2.80 (42.657) 95% CI of mean -1.08, 6.68 Mental health Mean Baseline Score (SD) (18.763) Mean change from baseline at exit visit (termination); (SD) (17.462) 95% CI of mean -3.51, 0.06 Time lost from workplace productivity and social activity (WPSA) Productivity Loss of work due to pain Mean Baseline Score (SD) 0.94 (0.200) Mean change from baseline at exit visit (termination); (SD) 0.19 (0.415) 95% CI of mean 0.12, 0.26 Social Loss of social activity due to pain Mean Baseline Score (SD) 0.77 (0.333) Mean change from baseline at exit visit (termination); (SD) 0.05 (0.414) 95% CI of mean 0.01, 0.10 Effective work Mean Baseline Score (SD) 0.91 (0.192) Mean change from baseline at exit visit (termination); (SD) 0.06 (0.210) 95% CI of mean 0.03, 0.09 BPI Worst pain score Mean Baseline Score (SD) 5.7 (1.73) Mean change from baseline at exit visit (termination); (SD) 1.9 (2.37) 95% CI of mean 1.7, 2.1 Pain interference score Mean Baseline Score (SD) 4.6 (2.30) Mean change from baseline at exit visit (termination); (SD) 1.5 (2.15) 95% CI of mean 1.3, 1.7 CES-D Total depression score Mean Baseline Score (SD) 13.1 (10.18) Mean change from baseline at exit visit (termination); (SD) -0.0 (8.76) 95% CI of mean -0.8, 0.8 POMS Total score Mean Baseline Score (SD) 28.8 (36.71)

4 Mean change from baseline at exit visit (termination); (SD) 2.9 (28.21) 95% CI of mean 0.4, 5.5 Tension/Anxiety Mean Baseline Score (SD) 9.4 (6.75) Mean change from baseline at exit visit (termination); (SD) 0.1 (5.63) 95% CI of mean -0.4, 0.6 Depression/Dejection Mean Baseline Score (SD) 9.6 (10.42) Mean change from baseline at exit visit (termination); (SD) 0.3 (8.59) 95% CI of mean -0.4, 1.1 Anger/Hostility Mean Baseline Score (SD) 7.0 (7.62) Mean change from baseline at exit visit (termination); (SD) 0.2 (6.68) 95% CI of mean -0.5, 0.8 Vigor/Vitality Mean Baseline Score (SD) 15.0 (6.89) Mean change from baseline at exit visit (termination); (SD) -1.2 (5.62) 95% CI of mean -1.7, -0.7 Fatigue/Inertia Mean Baseline Score (SD) 11.1 (6.78) Mean change from baseline at exit visit (termination); (SD) 1.3 (5.47) 95% CI of mean 0.8, 1.89 Confusion/Bewildered Mean Baseline Score (SD) 6.7 (5.29) Mean change from baseline at exit visit (termination); (SD) -0.2 (4.02) 95% CI of mean (-0.5, 0.2) Most Frequent Adverse Events (>5% of Subjects) On-Therapy LTG N = 491 Any Event, n (%) 396 (81) Any Rash (includes all rash related terms) 70 (14) Rash 30 (6) Dizziness 55 (11) Headache 48 (10) Nausea 42 (9) Arthralgia 43 (9) Balance Disorder 33 (7) Upper Respiratory Tract Infection 28 (6) Edema Peripheral 28 (6) Back Pain 27 (5) Pain in Extremity 26 (5) Hypertension 26 (5) Serious Adverse Events On Therapy n (%) [n considered by the investigator to be related to study medication] LTG N = 491 Subjects with any SAEs 1, Includes both fatal and non-fatal events 60 (12) [6] Congestive heart failure 6 (1) [0] Coronary artery disease 5 (1) [0] Myocardial Infarction 5 (1) [0] Atrial fibrillation 4 (<1) [1] Sinus bradycardia 1 (<1) [1] Angina pectoris 1 (<1) [0] Angina unstable 1 (<1) [0] Bradyarrhythmia 1 (<1) [0] Cardiac disorder 1 (<1) [0]

5 Myocardial ischemia 1 (<1) [0] Ventricular fibrillation 1 (<1) [0] Chest pain 7 (1) [0] Asthenia 1 (<1) [0] Impaired healing 1 (<1) [0] Pyrexia 1 (<1) [0] Bronchitis 2 (<1) [0] Cellulitis 2(<1) [0] Gangrene 1 (<1) [0] Influenza 1 (<1) [0] Localized infection 1 (<1) [0] Pneumonia 1 (<1) [0] Pneumonia bacterial 1 (<1) [0] Intestinal Obstruction 2(<1) [0] Vomiting 2(<1) [0] Diarrhea 1 (<1) [0] Gastric ulcer 1 (<1) [0] Gastroesophageal reflux disease 1 (<1) [1] Peptic ulcer hemorrhage 1 (<1) [0] Cerebrovascular accident 2 (<1) [0] Syncope 2 (<1) [1] Cerebral infarction 1 (<1) [0] Diabetic hyperosmolar coma 1 (<1) [0] Dizziness 1 (<1) [0] Ligament injury 1 (<1) [0] Lower limb fracture 1 (<1) [0] Neck injury 1 (<1) [0] Pelvic fracture 1 (<1) [0] Radius fracture 1 (<1) [0] Road traffic accident 1 (<1) [0] Dehydration 1 (<1) [0] Diabetic foot 1 (<1) [0] Hypoglycemia 1 (<1) [0] Hypokalemia 1 (<1) [0] Hypovolemia 1 (<1) [0] Metabolic acidosis 1 (<1) [0] Asthma 1 (<1) [0] Bronchospasm 1 (<1) [0] Dyspnea 1 (<1) [0] Pulmonary edema 1 (<1) [0] Respiratory distress 1 (<1) [0] Respiratory failure 1 (<1) [0] Musculoskeletal chest pain 1 (<1) [0] Neck pain 1 (<1) [0] Breast cancer 1 (<1) [0] Colon cancer 1 (<1) [0] Cholecystitis 2 (<1) [0] Renal failure acute 1 (<1) [0] Urethral obstruction 1 (<1) [0] Lymphangitis 1 (<1) [0] Orthostatic hypotension 1 (<1) [0] Anemia 1 (<1) [0] Vestibular disorder 1 (<1) [0] Mental status change 1 (<1) [1] Rash Toxic skin eruption 1 (<1) [1]

6 Subject with fatal SAEs 1 (<1) [0] Myocardial infarction 1 (<1) [0] Note: a subject may have experienced more than one SAE. Conclusion: Adverse events were reported in 396 (81%) of the subjects, with the most frequently reported events being Any Rash, dizziness and headache. Serious adverse events were reported in 60 (12%) of the subjects with the most frequently reported being congestive heart failure, coronary artery disease and myocardial infarction. One death was reported. Publications: No publication Date Updated: 23-May-2005